Integrin-αvβ3 as a Therapeutic Target in Glioblastoma: Back to the Future?

Abstract

Glioblastoma (GBM), the most common primary malignant brain tumor, is associated with a dismal prognosis. Standard therapies including maximal surgical resection, radiotherapy, and temozolomide chemotherapy remain poorly efficient. Improving GBM treatment modalities is, therefore, a paramount challenge for researchers and clinicians. GBMs exhibit the hallmark feature of aggressive invasion into the surrounding tissue. Among cell surface receptors involved in this process, members of the integrin family are known to be key actors of GBM invasion. Upregulation of integrins was reported in both tumor and stromal cells, making them a suitable target for innovative therapies targeting integrins in GBM patients, as their impairment disrupts tumor cell proliferation and invasive capacities. Among them, integrin-αvβ3 expression correlates with high-grade GBM. Driven by a plethora of preclinical biological studies, antagonists of αvβ3 rapidly became attractive therapeutic candidates to impair GBM tumorigenesis. In this perspective, the advent of nuclear medicine is currently one of the greatest components of the theranostic concept in both preclinical and clinical research fields. In this review, we provided an overview of αvβ3 expression in GBM to emphasize the therapeutic agents developed. Advanced current and future developments in the theranostic field targeting αvβ3 are finally discussed.

Identification of Prognostic Genes in Gliomas Based on Increased Microenvironment Stiffness

“…The key roles of the integrin family in glioblastoma have been studied intensively, and integrin-α5β3 is known to be a major therapeutic target [ 44 ]. ITGA5 and ITGB1 form a receptor for fibronectin and have mainly been explored for their roles in cell-surface mediated signaling.…”

“…Moreover, both the epigenetic and transcriptional levels of ITGA5 are effective in predicting TMZ and bevacizumab resistance, revealing the novel roles of ITGA5 in predicting the treatment outcomes of glioma [ 49 ]. To eliminate the malignance of GBM with highly expressed integrin-α5β3, various anti-integrin agents, such as RGD-containing peptides, have been developed; RGD peptides can be used as selective carriers to deliver anti-cancer drugs, and have shown strong anti-glioma efficacy [ 44 ]. Moreover, because of the high affinity between RGD peptides and integrin, several targeting radiotracers have been developed for phenotypic imaging and radiotherapy [ 44 , 50 ].…”

Observation of the protein expression level via naked eye: Pt clusters catalyze non-color molecules into brown-colored molecules in cells

“…Integrins are a superfamily of cell adhesion receptors that can bind to extracellular matrix ligands, surface ligands, artificial ligands, and the transmembrane αβ heterodimers with at least 18 α and 8 β subunits and are capable of forming at least 24 different heterodimers ( Takada et al, 2007 ; Marelli et al, 2013 ; Chen et al, 2016 ; Demircioglu and Hodivala-Dilke, 2016 ; Reis et al, 2022 ). Among them, α v β 3 can mediate adhesion, malignant transformation, tumor growth, invasion, and metastasis at different stages of cancer ( Knowles et al, 2013 ; Tang et al, 2020 ) and is involved in the regulation of angiogenesis ( Danhier et al, 2012 ; Echavidre et al, 2022 ). α v β 3 is highly expressed in tumors rather than normal tissues ( Pu et al, 2019 ; Nakagawa et al, 2022 ), and its expression is associated with the disease progression of various tumor types ( Lin et al, 2018 ; Cheng et al, 2021 ).…”

Internalisation of RGD-Engineered Extracellular Vesicles by Glioblastoma Cells

“…It has been established that the GBM cell surface is characterised by the overexpression of transmembrane receptors—integrins—that facilitate cell-to-cell and cell-to-extracellular matrix (ECM) adhesion, resulting in the increased invasiveness and survival of glioma cells [ 18 ]. Integrins, in particular, αvβ3 and αvβ5, have been proposed as attractive molecules for targeted therapies, mainly for their ability to recognise the RGD (Arginine–Glycine–Aspartate) polypeptide [ 19 , 20 , 21 ]. With current bioengineering technologies, various peptides can be introduced to EV surface membranes, enhancing particle binding to and internalisation by the cells of interest [ 12 , 22 , 23 ].…”